Method and device for producing different solid dosage forms

ABSTRACT

The invention relates to a process and an apparatus for producing solid dosage forms by molding plastic active ingredient-containing mixtures with use of a continuously operating molding tool with two parts which cooperate to mold the plastic mixture, with at least one part having a plurality of depressions to receive and mold the plastic mixture, wherein one part has at least two groups, which differ in volume and/or shape, of depressions. Dosage forms which differ in shape or size are obtained in one step.

The present invention relates to a process for producing solid dosageforms by molding a plastic active ingredient-containing mixture with useof a continuously operating molding tool with two parts which cooperateto mold the plastic mixture, with at least one part having a pluralityof depressions to receive and mold the plastic mixture.

The production of solid dosage forms, in particular pharmaceuticaldosage forms or foodstuffs or food supplements for humans and animals,by calendering an active ingredient-containing melt is disclosed in anumber of publications. This process is based on the embedding of anactive ingredient in a melt composed of a carrier, e.g. fatty substancesor physiologically tolerated polymers. This usually entails an activeingredient-containing melt or an active ingredient-containing plasticmixture being produced in a mixer and/or extruder and then being fedinto a molding tool, e.g. a calender with molding rolls. The calendercomprises a pair of counter-rotating molding rolls which have on theirsurface engravings (depressions) which, for example, correspond to theshape of one half of a tablet. The tablet molding takes place in theregion of contact of the two rolls by combination of the tabletcomposition in one depression on one roll with that in the oppositedepression on the other roll. It is also conceivable to combine amolding roll with depressions and a smooth roll or a smooth belt to moldsuch plastic mixtures. The production of tablets by this process isdescribed in general by DE-A-17 66 546 and U.S. Pat. No. 4,880,585;DE-A-44 46 467 describes the production of lenticular tablets andWO-96/19962 the production of divisible tablets. These processes haveconsiderable advantages compared with the conventional production ofdosage forms by, for example, tableting powders and granules underpressure. Thus, melt extrusion with subsequent molding by calenderingcombines a plurality of stages such as metering in, mixing,plasticizing, molding and singulation, in a single continuous processand thus permits a high output, constant quality and extensive freedomin the shaping, makes few demands on the treatment of the precursors andthus makes it possible to produce large numbers of items economically.These advantages are displayed fully only with really large numbers ofitems, because of the many parameters requiring optimization in so manystages.

There is an observable trend toward diversification in relation to thedosage and the administration form of active ingredients in manysubsectors of the drugs market. This diversification is caused interalia by increasing demands on the uniformity of the active ingredientdose, which is not as a rule ensured by divisible tablets. The provisionof a large number of dosages of the same active ingredient is required,for example, when stabilizing patients on particular active ingredients,e.g. for cardiovascular disorders, when different groups of patientshave different dose requirements/response times, e.g. adults/children. Alarge number of dosage forms differing in the dose of active ingredientis also required for active ingredients with a small therapeutic indexand for active ingredients with several medical indications. Thus, forexample, in the case of the active ingredient acetylsalicylic acid thedose on use in tablets for pain is 500 mg, whereas the same activeingredient is administered in a dose of only 100 mg as plateletaggregation inhibitor. It is also desirable in many cases to be able tooffer several embodiments of an active ingredient preparation, e.g.divisible or nondivisible, lenticular or oblong tablets, in order tomeet the requirements of different markets or contract manufacture.

The manufacture of such a large number of different dosage forms has todate been possible only by conventional tableting, with thedisadvantages which are known. In addition, with conventional tabletingit is possible to achieve different dosages only by different tabletformulas for separate manufacture, and the simultaneous production ofdifferent dosages/forms in one tableting machine have not previouslybeen disclosed and is imaginable only with great difficulty.

It is an object of the present invention to provide a process and anapparatus which make it possible quickly, efficiently andcost-effectively to produce simultaneously a large number of differentdosages and/or shapings of an active ingredient.

The present invention therefore relates to a process for producing soliddosage forms by molding a plastic active ingredient-containing mixturewith use of a continuously operating molding tool with two parts whichcooperate to mold the plastic mixture, with at least one part having aplurality of depressions to receive and mold the plastic mixture,wherein one part has at least two groups, which differ in volume and/orshape, of depressions.

DESCRIPTION OF THE FIGURES

FIG. 1 shows an axial section through a pair of rolls W1 and W2 withdifferent depressions V1, V1T, V2, V3, V4 and V5.

FIG. 2 shows an axial section through a pair of rolls W1′ and W2.

FIG. 3 shows a detail of the rolling from the molding rolls used in theexample. The groups of depressions are arranged in lanes 1 to 8.

The term “dosage form” herein designates any form for administration ofactive ingredients to humans, animals or plants. The dosage formsobtained according to the invention are suitable in particular for oralor rectal administration or as implantable active ingredient depots inhumans and animals. Particularly preferred dosage forms are tablets ofany shape, coated tablets, pellets and suppositories.

It is possible to obtain by the process according to the invention aplurality of different dosage forms in one step. Different dosage formsare dosage forms which differ in volume (and thus in active ingredientdosage) and/or in the shape (e.g. lenticular, elongate, round;divisible, nondivisible etc.).

Whereas in conventional tableting using a tableting machine the densityand thus the volume of the tablet depends not only on the mold used butalso on the compressive force, in the molding of dosage forms usingcontinuous molding tools such as, for example, calenders with moldingbelts or rolls which have a defined spacing or are in contact, thevolume of the dosage form depends directly on the volume of thedepressions in the molding tool. Thus, in this process, the activeingredient content of the dosage form with a given formula (i.e. fixedpercentage active ingredient content) depends directly on the volume ofthe depressions in the molding tools. This is possible because in theprocess according to the invention there is use of a plastic activeingredient-containing mixture which is preferably essentiallyincompressible and whose density can therefore, in contrast to thegranules and powders employed in conventional tableting, be keptconstant within narrow limits. It is therefore possible with the processdescribed herein to produce, by using continuous molding tools with twocooperating parts, at least one of which parts has depressions whichdiffer in volume and/or differ in shape, dosage forms which differ inactive ingredient dosage and/or differ in shape from one formula in onestep. For this purpose, the molding tool in the process according to theinvention is fed with a plastic active ingredient-containing mixture ofa composition which is as constant as possible. The different dosageforms are formed or molded solely because of the different groups ofdepressions in the molding tool.

To produce the plastic mixture it is necessary to mix the constituents,namely at least one thermoplastic, physiologically tolerated, usuallypolymeric, binder and at least one active ingredient and, whereappropriate, conventional additives and convert them into a plasticmixture, preferably in the absence of a solvent. The formation of theplastic mixture can take place by melting or else by kneading, mixing orhomogenizing below the melting point of the binder. These process stepscan be carried out in a manner known per se, for example as described inEP-A-0 240 904, EP-A-0 337 256, EP-A-0 358 105, WO 97/15290 and WO97/15291. The contents of these publications are incorporated herein byreference.

The components can be first mixed and then converted into the plasticstate and homogenized. However, it has proven preferable, especiallywhen sensitive active ingredients are used, firstly for the polymericbinder, where appropriate together with conventional pharmaceuticaladditives, to be converted into the plastic state and premixed,operating the apparatuses such as stirred vessels, agitators, solidsmixers etc. where appropriate alternately, and then for the sensitiveactive ingredient(s) to be mixed (homogenized) in intensive mixers inthe plastic phase with very short residence times. The activeingredient(s) can be employed in solid form or as solution ordispersion.

The plasticization and mixing take place in an apparatus usual for thispurpose. Particularly suitable ones are extruders or heatable containerswith agitators, e.g. kneaders (such as of the type mentioned below).

It is also possible to use as mixing apparatus the types employed formixing in plastics technology. Suitable apparatuses are described, forexample, in “Mischen beim Herstellen und Verarbeiten von Kunststoffen”,H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing apparatuses areextruders and dynamic and static mixers, and stirred vessels,single-shaft stirrers with stripper mechanisms, especially paste mixers,multishaft stirrers, especially PDSM mixers, solids mixers and,preferably, mixer/kneader reactors (e.g. ORP, CRP, AP, DTB supplied byList or Reactotherm supplied by Krauss-Maffei or Ko-kneader supplied byBuss), trough mixers or internal mixers or rotor/stator systems (e.g.Dispax supplied by IKA).

In the case of sensitive active ingredients, it is preferable first forthe polymeric binder to be converted into the plastic state in anextruder and then for the active ingredient to be admixed in amixer/kneader reactor. On the other hand, with less sensitive activeingredients, a rotor/stator system can be employed for vigorouslydispersing the active ingredient.

The mixing apparatus is charged continuously or batchwise, depending onits design, in a conventional way. Powdered components can be introducedin a free feed, e.g. via a weigh feeder. Plastic compositions can be fedin directly from an extruder or via a gear pump, which is particularlyadvantageous if the viscosities and pressures are high. Liquid media canbe metered in by a suitable pump unit.

The mixture obtained by mixing and converting the binder, whereappropriate the active ingredient and, where appropriate, theadditive(s) into the plastic state is pasty or viscous (plastic) and istherefore extrudable. The binder should preferably be soluble orswellable in a physiological environment. Examples of suitable bindersare:

polyvinyllactams, in particular polyvinylpyrrolidone (PVP), copolymersof vinyllactams such as N-vinylpyrrolidone, N-vinylpiperidone andN-vinyl-ε-caprolactam, but especially N-vinylpyrrolidone, with(meth)acrylic acid, (meth)acrylic esters, vinyl esters, especially vinylacetate, copolymers of vinyl acetate and crotonic acid, partlyhydrolyzed polyvinyl acetate, polyvinyl alcohol, poly(hydroxyalkylacrylates), poly(hydroxyalkyl methacrylates), polyacrylates andpolymethacrylates, copolymers of dimethylaminoethyl acrylates andmethacrylic esters (e.g. Eudragit types), polyalkylene glycols such aspolypropylene glycols and polyethylene glycols (e.g. polyethylene glycol6000), copolymers of methyl methacrylate and acrylic acid, celluloseesters, cellulose ethers, in particular methylcellulose andethylcellulose, hydroxyalkylcelluloses, in particularhydroxypropylcellulose or hydroxypropylmethylcellulose,hydroxyalkylalkylcelluloses, in particular hydroxypropylethylcellulose,cellulose phthalates, in particular cellulose acetate phthalate andhydroxypropylmethylcellulose phthalate, and mannans, in particulargalactomannans.

It is also possible to use gelatin and biodegradable polymers such aspolyhydroxyalkanoates, e.g. polyhydroxybutyric acid, polylactic acid,polyamino acids, e.g. polylysine, polyasparagine, polydioxanes andpolypeptides.

Preferred polymeric binders are polyvinylpyrrolidone, copolymers ofN-vinylactams, in particular N-vinylpyrrolidone, and vinyl esters,copolymers of N-vinyllactams, in particular N-vinylpyrrolidone, with(meth)acrylic esters, poly(hydroxyalkyl acrylates), poly(hydroxyalkylmethacrylates), polyacrylates, polymethacrylates, alkylcelluloses andhydroxyalkylcelluloses, in particular hydroxypropylcellulose andhydroxypropylmethylcellulose.

Binders which are advantageous for use as plastic binder are thosehaving a K value (method of H. Fikentscher, Cellulose-Chemie 13 (1932),pp. 58-64 and 71-74) in the range between 10 and 100, in particularbetween 20 and 80.

The polymeric binder must be convertible into a plastic state in thecomplete mixture of all the components in the range of from 50 to 160°C., preferably 60 to 130° C. The glass transition temperature of themixture must therefore be below 180° C., preferably below 150° C. Ifnecessary, it is reduced by conventional pharmacologically acceptableplasticizing auxiliaries. The amount of plasticizer does not exceed 30%of the total weight of binder and plasticizer in order to formstorage-stable drug forms which show no cold flow. However, the mixturepreferably contains no plasticizer.

Examples of such plasticizers are:

long-chain alcohols, ethylene glycol, propylene glycol, glycerol,trimethylolpropane, triethylene glycol, butanediols, pentanols such aspentaerythritol, hexanols, polyethylene glycols, polypropylene glycols,polyethylene/propylene glycols, silicones, aromatic carboxylic esters(e.g. dialkyl phthalates, trimellitic esters, benzoic esters,terephthalic esters) or aliphatic dicarboxylic esters (e.g. dialkyladipates, sebacic esters, azelaic esters, citric and tartaric esters),fatty acid esters such as glycerol mono-, di- or triacetate or sodiumdiethyl sulfosuccinate. The concentration of plasticizer is generallyfrom 0.5 to 15, preferably 0.5 to 5, % of the total weight of themixture.

Conventional pharmaceutical auxiliaries, whose total amount can be up to100% of the weight of the polymer, are, for example,

extenders and bulking agents such as silicates or diatomaceous earth,magnesium oxide, aluminum oxide, titanium oxide, methylcellulose, sodiumcarboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch,potato flour, polyvinyl alcohol, in particular in a concentration offrom 0.02 to 50, preferably 0.20 to 20, % of the total weight of themixture;

lubricants and release agents such as magnesium, aluminum and calciumstearates, talc and silicones, and animal or vegetable fats, especiallyin hydrogenated form and those which are solid at room temperature.These fats preferably have a melting point of 50° C. or above.Triglycerides of C₁₂, C₁₄, C₁₆ and C₁₈ fatty acids are preferred. It isalso possible to use waxes such as carnauba wax. These fats and waxesmay be admixed advantageously alone or together with mono- and/ordiglycerides or phosphatides, especially lecithin. The mono- anddiglycerides are preferably derived from the abovementioned fatty acidtypes. The total amount of lubricants and release agents is preferably0.1 to 5% of the total weight of the composition for each layer;

flow regulators, e.g. Aerosil, in an amount of from 0.1 to 5% of thetotal weight of the mixture;

dyes, such as azo dyes, organic or inorganic pigments or dyes of naturalorigin, with preference for inorganic pigments in a concentration offrom 0.001 to 10, preferably 0.5 to 3, % of the total weight of themixture;

stabilizers such as antioxidants, light stabilizers, hydroperoxidedestroyers, radical scavengers, stabilizers against microbial attack.

It is also possible to add wetting agents, preservatives, disintegrants,adsorbents and mold release agents (cf., for example, H. Sucker et al.,Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).

Auxiliaries include for the purpose of the invention substances forproducing a solid solution with the active pharmaceutical ingredient.Examples of these auxiliaries are pentaerythritol and pentaerythritoltetraacetate, polymers such as polyethylene oxides and polypropyleneoxides and their block copolymers (poloxamers), phosphatides such aslecithin, homo- and copolymers of vinylpyrrolidone, surfactants such aspolyoxyethylene 40 stearate, and citric and succinic acids, bile acids,sterols and others as indicated, for example, in J. L. Ford, Pharm. ActaHelv. 61, (1986) 69-88.

Pharmaceutical auxiliaries are also regarded as being bases and acidsadded to control the solubility of an active ingredient (see, forexample, K. Thoma et al., Pharm. Ind. 51 (1989), 98-101).

The only preconditions for the suitability of auxiliaries are adequatethermal stability and compatibility with the active ingredient used.

Active ingredients mean for the purpose of the invention all substanceswith a desired effect, especially pharmaceutical effect, on the human,animal or plant organism and minimal side effects, as long as theirdecomposition under the processing conditions is negligible. The amountof active ingredient per dose unit and the concentration may vary withinwide limits depending on the activity and the release rate. The onlycondition is that they suffice to achieve the desired effect. Thus, theconcentration of active ingredient can be in the range from 0.001 to 95,preferably from 20 to 80, in particular 30 to 70, % by weight. It isalso possible to employ combinations of active ingredients. Activeingredients for the purpose of the invention also include vitamins andminerals, and plant treatment agents and insecticides. The vitaminsinclude the vitamins of the A group, the B group, by which are meantbesides B₁, B₂, B₆ and B₁₂ and nicotinic acid and nicotinamide alsocompounds with vitamin B properties such as adenine, choline,pantothenic acid, biotin, adenylic acid, folic acid, orotic acid,pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoicacid, and vitamin C, vitamins of the D group, E group, F group, H group,I and J groups, K group and P group. Active ingredients for the purposeof the invention also include therapeutic peptides and vaccines.

The novel process is suitable, for example, for processing the followingactive ingredients or pharmacologically active salts thereof:

acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir,alfacalcidol, allantoin, allopurinol, alprazolam, ambroxol, amikacin,amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine,amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine,benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol,bromazepam, bromhexine, bromocriptine, budesonide, bufexamac,buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine,carbidopa, carboplatin, cefachlor, cefadroxil, cefalexin, cefazoline,cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime,chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone,choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride,cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam,clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid,cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol,dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxycycline, enalapril, ephedrine, epinephrine,ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol,etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate,fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine,fluorouracil, fluoxetine, flurbiprofen, folinic acid, furosemide,gallopamil, gemfibrozil, gentamicin, Gingko biloba, glibenclamide,glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin,haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen,imipenem, imipramine, indomethacin, iohexol, iopamidol, isosorbidedinitrate, isosorbide mononitrate, isotretinoin, itraconazole,ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose,lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel,levothyroxine, lidocaine, lipase, lisinopril, loperamide, lorazepam,lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa,methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam,minocycline, minoxidil, misoprostol, morphine, multivitaminmixtures orcombinations and mineral salts, N-methylephedrine, naftidrofuryl,naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine,nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine,nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline,nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,pantothenic acid, paracetamol, penicillin G, penicillin V,pentoxifylline, phenobarbital, phenoxymethylpenicillin, phenylephrine,phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine,pravastatin, prazepam, prazosin, prednisolone, prednisone, propafenone,propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine,ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin,rutoside, saccharin, salbutamol, salcatonin, salicylic acid, selegiline,simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam,sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur,teprenone, terazosin, terbutaline, terfenadine, tetracycline,theophylline, thiamine, ticlopidine, timolol, tranexamic acid,tretinoin, triamcinolone acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E,zidovudine.

Preferred active ingredients are ibuprofen (as racemate, enantiomer orenriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid,verapamil, paracetamol, nifedipine, captopril, omeprazole, ranitidine,tramadol, ciclosporin, trandolapril and therapeutic peptides.

It is possible specifically for solid solutions to be formed. The term“solid solutions” is familiar to the skilled worker, for example fromthe literature cited at the outset. In solid solutions of activepharmaceutical ingredients in polymers, the active ingredient is in theform of a molecular dispersion in the polymer.

On extrusion of the plastic mixture it is advantageous to choose thetemperature, viscosity and extrusion rate so as to obtain a coherent,self-supporting extrudate. This generally results in continuousproduction of an extrudate preferably with a constant cross section. Ithas proven advantageous in many cases to extrude on a downward inclineand/or where appropriate to provide a guide channel for transporting theextrudate in order to ensure safe transport and prevent the extrudatebeing torn off. Depending on the number and compatibility of the activeingredients to be employed, it is also possible and advantageous toemploy multilayer extrudates, e.g. coextrudates, as described in WO96/19963 in the process according to the invention.

The plastic active ingredient-containing mixture described above is fedin the process according to the invention to a continuously operatingmolding tool. This comprises two parts which cooperate to mold theplastic mixture, at least one of these parts having depressions toreceive and mold the plastic mixture. The solid dosage forms are usuallyproduced by feeding the plastic active ingredient-containing mixtureinto the molding tool in such a way that the plastic mixture is forcedinto the depressions in the part (or parts) of the molding tool and thusmolded to the dosage form.

Depressions mean in this connection recesses or engravings on thesurface of the part or parts of the molding tool to receive and mold theplastic active ingredient-containing mixture. The outer margin of thedepression on the surface of the particular part is referred to asoutline. To make it possible to remove the dosage forms after themolding from the part or parts with depressions, the largest crosssection of the depressions is usually on the surface of the particularpart, e.g. the outer surface of a molding roll. Downstream of themolding tool there is, where appropriate, also a stripper device, e.g. astripper roll, stripper brush or the like, which makes possible orfacilitates the removal of the dosage forms and/or cleans the moldingtool, in particular the parts thereof with depressions.

Particularly suitable molding tools are those having belts and/ormolding rolls as cooperating parts, with at least one of the beltsand/or at least one of the molding rolls having depressions to receiveand mold the plastic mixture. Suitable belts are elastic belts andarticulated belts made of polymeric materials, where appropriate withfillers, and/or metallic materials. Belts of these types are usuallyguided and conveyed by means of guide rolls and/or guide wheels.Suitable belts and belt-containing devices are generally disclosed, forexample, in EP-A-0 358 105, the contents of which are herebyincorporated by reference. Belts and/or molding rolls of this thesetypes are preferably disposed in calenders, in which case there isusually combination of at least two belts or two molding rolls or onemolding roll with one belt.

It is preferred to use as one part of the molding tool a molding rollwhich has depressions and is preferably disposed in a calender. It canbe combined with a smooth second part, e.g. with a smooth belt, a smoothroll or a smooth wall. This results in dosage forms which are flat onone side and have the shape of the depression on the other side.

The molding tools preferably used for the process according to theinvention comprise two cooperating parts having depressions.

Thus, in a particularly suitable embodiment of the process according tothe invention, a molding roll having depressions is likewise employed asthe other part of the molding tool, with the molding rolls rotating inopposite directions and the outlines of the depressions in one moldingroll essentially coinciding pairwise with the outlines of thedepressions in the other molding roll in the gap between the moldingrolls.

The gap referred to here is the region in which the two parts of themolding tool come closest together, irrespective of whether the surfaces(e.g. outer surfaces) of the parts make contact or are spaced apart.

Counter-rotating molding rolls of this type are preferably disposed in acalender. The plastic mixture can be introduced, for example, by meansof a filling wedge into the trough-like space formed between the twomolding rolls. The plastic mixture is then taken up and molded bydepressions in the counter-rotating molding rolls. The space between thetwo molding rolls is preferably chosen so that the surfaces of themolding rolls form a small gap, preferably of less than 5 mm and, inparticular, of less than 1 mm, or the surfaces of the molding rolls makecontact. If it is wished to obtain dosage forms which have minimalprojecting burrs or flashes, it is advantageous to adjust the spacebetween the parts of the molding tool, e.g. the molding rolls, to be assmall as possible so the resulting gap is as narrow as possible. If itis wished to obtain the dosage forms as coherent strips of dosage forms,it may be advantageous to choose a somewhat larger space between theparts of the molding tool, and thus a far larger gap, or to provide inthe peripheral direction between the depressions on the outer surface ofthe molding roll a connecting channel which is likewise filled with theplastic mixture during molding of the dosage form, and thus connectsadjacent dosage forms with connecting flashes or bars to form strips(“string of beads”) or ribbons with a plurality of rows of dosage formsconnected together.

The depressions of the part (or parts) of the molding tool are to beassigned according to the invention to at least two groups, with thedepressions in different groups differing in volume and/or shape. Thenumber of depressions on a part is usually more than 5, in particularmore than 10 or more than 50. It is immaterial how many depressionsbelong to the respective group and how the depressions in a group aredisposed on the part.

Different groups of depressions may differ in the shape of the outlines,e.g. into elongate, elliptical or round, in the size of the outlines,e.g. large or small, and/or in the shape of the depressions themselves,e.g. in the volume, in the radii of curvature of the limiting surfacesof the depressions, e.g. shallow lenticular, semicircular, hemisphericaland/or by the presence of bars resulting in the formation of scores inthe dosage forms and thus in divisible dosage forms.

It is thus possible in one embodiment of the process according to theinvention for one part of the molding tool to have a plurality of groupsof depressions, in which case, for example, a first group results in themolding of round dosage forms, a second group results in the formationof elongate dosage forms, a third group results in the molding oflenticular dosage forms and a fourth group results in the molding ofdivisible dosage forms. In another embodiment, one part of the moldingtool may have depressions which differ essentially in volume, e.g. smalllenticular and large lenticular dosage forms.

On use of two molding rolls it is possible to combine one molding rollW1 with uniform depressions V1 with a second molding roll W2 which hastwo groups of depressions V1 and V2. This arrangement can be usedaccording to the invention to produce different dosage formspredetermined by the combinations V1 (W1) and V1 (W2) or V1 (W1) and V2(W2).

On use of a molding roll or of a pair of molding rolls it may beadvantageous for the depressions in different groups to be arranged onseparate lanes on the molding roll. Lanes mean in this connection inparticular an arrangement in which the centers of gravity of thedepressions in one group are arranged consecutively in the peripheraldirection on the surface of the roll. The individual lanes are, whereappropriate, arranged spaced apart in the axial direction.

This arrangement permits removal of the different groups of resultingdosage forms after the molding or after sufficient cooling in separategroups from the molding tool. It is thus possible to obtain the dosageforms sorted into groups in a simple manner. Removal of the dosage formsin separate groups can take place, for example, by separate collectionof the dosage forms in each group in separate containers, whereappropriate with the aid of separate funnels, deflector plates, suctionapparatuses and similar devices for each group, if the dosage formsemerge singly from the depressions or can be removed singly from thedepressions, for example with the stripper devices described previously.Removal in separate groups takes place particularly easily if the dosageforms are obtained as strips or ribbons connected by connecting flashesor connecting bars. Singulation of the dosage forms advantageously thentakes place in separate groups, e.g. by cutting the ribbons, and theyare further processed where appropriate, such as, for example, deflashedand/or rounded off, as described in DE-A-196 29753, the contents ofwhich are incorporated herein by reference. The removal of the differentdosage forms in separate groups makes subsequent sorting unnecessary andis particularly advantageous when the dosage forms differ in shape andvolume or weight so little that separation by sieving and/or classifyingby weight is difficult or impossible.

It is likewise advantageous to arrange the depressions of one group inlanes if, in addition to the plastic mixture, materials in the form ofsheets are introduced in each case between melt and molding roll ormolding belt, which makes it possible for molding of the plastic mixtureto dosage forms to take place at the same time as the coating and/orpackaging of the dosage form, as described in WO-96/19963, the contentsof which are incorporated herein by reference.

Alternatively, the dosage forms are collected and then sorted intogroups. In a preferred embodiment, dosage forms sorted into groups areobtained by sieving and/or classifying by weight the resulting dosageforms. This is particularly suitable when the different dosage formsdiffer sufficiently in shape and/or volume or weight. It may benecessary, where appropriate, for singulation of the resulting dosageforms to take place only after removal from the molding tool, beforesorting by sieving and/or classifying by weight if possible. This isparticularly worthwhile when the dosage forms are still wholly or partlyconnected together on emergence from the molding tool. Processes forsorting dosage forms by sieving and/or classifying by weight are knownto the skilled worker.

The resulting different dosage forms can, where appropriate, be furtherprocessed, e.g. provided with a coating, together or in separate groupsin analogy to known processes in which uniform dosage forms have beenobtained.

In a specific embodiment of the process according to the invention thereis use of two molding rolls whose depressions are shaped and arranged sothat both a first and a second orientation are possible for the moldingrolls, it being possible to convert the first orientation into thesecond orientation by rotation of one of the two molding rolls by 180°relative to at least one axis perpendicular to the long axis of thismolding roll. This means that one of the molding rolls can be removedfrom the molding tool and reinserted so that the original left-hand endis now located on the right; it is then necessary, where appropriate, toresynchronize the rolls. Compatibility of the depressions in the twoorientations is ensured, for example, when the outlines of thedepressions are disposed to be radially symmetrical relative to at leastone point on one rolling of the outer surfaces of each molding roll.

The arrangement of the outlines described above is particularlyworthwhile when the combinations of depressions in the secondorientation differ from those in the first orientation. This can beillustrated by the case shown in FIGS. 1 and 2, where one pair ofcounter-rotating molding rolls W1 and W2 is used, with molding roll W1having four lanes of depressions V1, V1T, V2 and V3 and molding roll W2having alternating lanes V4, V5, V4 and V5. The depressions V1, V2, V3,V4 and V5 differ in shape and volume. V1 and V1T differ by the presenceof a bar in V1T, which leads to the formation of a score and thus to adivisible dosage form. All the depressions on W1 and W2 should have thesame outlines and be arranged in equal number equidistantly in sequencein the peripheral direction on the particular lane. The spaces betweenthe lanes and the spaces between the outer lanes and the ends of themolding roll are each chosen to be the same. The dosage forms possiblewith such a combination of molding rolls are depicted in Tables 1 and 2.In this case, W1′ represents the molding roll W1 which has been rotatedby 180° as described above.

This illustration demonstrates that a large number of different dosageforms can be produced in this way with one apparatus.

TABLE 1 (first orientation) W1 Lane 1 Lane 2 Lane 3 Lane 4 V1 V1T V2 V3W2 Lane 1 Lane 2 Lane 3 Lane 4 V4 V5 V4 V5 Resulting dosage V1 + V4V1T + V5 V2 + V4 V3 + V5 form

TABLE 2 (second orientation) W1′ (rotated by Lane 4 Lane 3 Lane 2 Lane 1180°) V3 V2 V1T V1 W2 Lane 1 Lane 2 Lane 3 Lane 4 V4 V5 V4 V5 Resultingdosage V3 + V4 V2 + V5 V1T + V4 V1 + V5 form

The present invention likewise relates to an apparatus for producingvarious dosage forms by molding a plastic active ingredient-containingmixture, which comprises two parts which cooperate to mold a plasticmixture, with at least one part having a plurality of depressions toreceive and mold the plastic mixture, wherein one part has at least twogroups of depressions which differ in volume and/or shape. In thisconnection, the terms “part”, “depressions”, “plastic mixture” and“groups of depressions” have the meanings described above. The apparatusaccording to the invention is a continuously operating molding tool. Thestatements made above in connection with the process according to theinvention also apply, unless otherwise evident from the context, to theapparatus according to the invention.

The present invention relates in particular to an apparatus in which onepart is a molding roll with depressions. The present inventionparticularly preferably relates to an apparatus in which the other partis likewise a molding roll having depressions, in which case theoutlines of the depressions in the first molding roll and of thedepressions in the other molding roll essentially coincide pairwise inthe gap between the molding rolls on counter-rotation of the moldingrolls. In this connection, the terms “outlines”, “gap” and “essentiallycoincide” have the meaning defined above.

In a specific embodiment, the apparatus according to the inventioncomprises two counter-rotating molding rolls with depressions, whereinboth a first and a second orientation are possible for the moldingrolls, it being possible to convert the first orientation into thesecond orientation by rotating one of the two molding rolls by 180°relative to at least one axis perpendicular to the long axis of thismolding roll. In each of the two orientations, the outlines of thedepressions on one molding roll and of the depressions on the othermolding roll essentially coincide in the gap on counter-rotation of themolding rolls. The axis for the rotation by 180° is fixed by a point onthe surface of the roll which is the point of symmetry on rolling theouter surface, and its perpendicular projection onto the long axis ofthe roll. For the case of least symmetry (single point symmetry), thereis only one axis of rotation as defined in the previous description. Ifthere is a plurality of points of symmetry on rolling the outer surfacesof the molding rolls, there is an equal number of axes of rotation givenby the perpendicular projection of these points of symmetry onto thelong axis of the roll.

In the simplest case, all the depressions have the same outlines, e.g.round outlines, and the arrangement of the depressions on the twomolding rolls is mirror-symmetrical relative to a central planeperpendicular to the axis of the roll.

The following example is intended to illustrate the invention withoutrestricting it.

EXAMPLE

A plastic active ingredient-containing mixture which contained as activeingredient 48.0% by weight of verapamil hydrochloride and asthermoplastic physiologically tolerated polymeric binder a mixture of31.5% by weight of hydroxypropylcellulose supplied by Aqualon and 17.5%by weight of hydroxypropylmethylcellulose supplied by Colorcon and asauxiliary 3.0% by weight of lecithin was produced in a co-rotating twinscrew extruder (ZSK-40 from Werner & Pfleiderer, Stuttgart), and theactive ingredient-containing plastic mixture was extruded at an outputof 15 kg/h. The temperature of the plastic mixture was measured shortlybefore the die and was 120° C. Extrusion took place through a 12 cm-wideslit die. The extrudate was fed into a calender with twocounter-rotating molding rolls. Each of the molding rolls had 8 groupsof depressions arranged in 8 lanes (lanes 1 to 8), as depicted in FIG.3. Lanes 1 to 8 are arranged from left to right. The depressions in onegroup on one molding roll coincide in the gap on rotation with thedepressions in the corresponding group on the other molding roll. Theoutlines of group 1 (lane 1) were elliptical, those of group 2 (lane 2)and group 3 (lane 3) were elongate and those of groups 4 to 8 (lanes 4to 8) were round. A detail of the rolling of the outer surface of one ofthe two molding rolls is depicted at the top of FIG. 3.

The different dosage forms produced by calendering were removed ascoherent ribbon from the calender and were cooled on a downstreamconveyor belt. This was followed by singulation of the dosage forms, andthey were separated into groups 1 to 8 by classifying by weight. Theweight and the active ingredient content of the different dosage formsproduced by the process according to the invention using the apparatusaccording to the invention are shown in Table 3. The stated weight orthe stated active ingredient content of the dosage forms from thedifferent lanes represents the average weight from 100 dosage forms fromeach group.

TABLE 3 Active in- Weight¹⁾ gredient Shape of Shape of of the content¹⁾of Molding roll 1 the out- the dosage dosage the dosage Molding roll 2line form form [mg] form [mg] Lane 1 (group 1) elliptical almond- 408196 shaped Lane 2 (group 2) elongate rod-shaped 656 315 Lane 3 (group 3)elongate rod-shaped 325 156 Lane 4 (group 4) round lenticular 388 186Lane 5 (group 5) round lenticular 294 141 Lane 6 (group 6) roundlenticular 160 77 Lane 7 (group 7) round lenticular 81 39 Lane 8 (group8) round lenticular 22 11 ¹⁾average weight from 100 dosage forms fromeach group

We claim:
 1. A process for producing solid dosage forms, comprising i)mixing a thermoplastic, physiologically tolerated polymeric binder whichis convertible into a platic state in the range of from 50 to 160° C.,at least one active ingredient and, optionally, conventional additives,ii) converting the mixture into a plastic mixture, and iii)feeding theplastic mixture into a molding tool with two parts which cooperate tomold the plastic mixture, with at least one part having a plurality ofdepressions to receive and mold the plastic mixture, wherein one parthas at least two groups, which differ in volume and/or shape, ofdepressions.
 2. A process as claimed in claim 1, wherein a molding rollhaving depressions is used as one part of the molding tool.
 3. A processas claimed in claim 2, wherein a molding roll having depressions is usedas the other part of the molding tool, with the molding rolls rotatingin opposite directions and the outlines of the depressions in onemolding roll essentially coinciding pairwise with the outlines of thedepressions in the other molding roll in the gap between the moldingrolls.
 4. A process as claimed in claim 2, wherein the depressions indifferent groups are arranged on separate lanes on the molding roll. 5.A process as claimed in claim 4, wherein the resulting dosage forms areremoved in separate groups from the molding tool.
 6. A process asclaimed in claim 1, wherein the resulting dosage forms are sorted intogroups by sieving and/or classifying by weight.
 7. An apparatus forproducing various dosage forms comprising two molding rolls whichcooperate to mold a plastic mixture, a) the molding rolls having aplurality of depressions to receive and mold the plastic mixture, b) themolding rolls rotating in opposite directions and the outlines of thedepressions in one molding roll essentially coinciding pairwise with theoutlines of the depressions in the other molding roll in the gap betweenthe molding rolls, and c) at least one molding roll having at least twogroups of depressions which differ in volume and/or shape, wherein thedepressions are shaped and arranged on the surfaces of the rolls so thatboth a first and a second orientation of the molding rolls is possible,it being possible to convert the first orientation into the secondorientation by rotating one of the two molding rolls by 180° relative toat least one axis perpendicular to the long axis of this molding roll,and vice versa.